Inhalative Sedation

Similar to Diazepam, Midazolam as intravenous bolus administration (2-5 mg) has a rapid time of onset and a short duration of action. It is therefore especially suitable for the treatment of acutely agitated patients. Due to its higher hepatic extraction, Midazolam has a significantly shorter dwell time in the organism than Diazepam or Flunitrazepam. With mean elimination half-lives of 1.5 to 3.5 hours the substance for long-term sedation should be administered continuously. The basic need is between 3 and 15 mg/h. If even with higher Midazolam doses no sufficient sedation is reached, the analgosedation should be checked critically and if necessary replaced by other substances.

Accumulation and prolonged sedation are observed especially in obese patients or patients with low albumin level or renal insufficiency. With reduced liver perfusion, for example in hypovolemic shock or with sepsis, the metabolism of Midazolam is restricted. A prolonged duration of action can also be caused by accumulation of an active metabolite-hydroxymidazolam), especially with renal insufficient patients. A significant inhibition of the Midazolam metabolism with simultaneous administration of Propofol, Diltiazem and macrolide antibiotics has been described. Daily interruptions of the infusion and readjustment to the desired sedation depth are therefore to be recommended also when using Midazolam. Nevertheless, the time to the recovery of full consciousness after several days of sedation with Midazolam in clinical practice is scarcely predictable. To avoid withdrawal syndromes, at the end of the therapy Midazolam should be gradually reduced.

Lorazepam is predominantly used to initiate the treatment of severe states of neurotic anxiety and excitement (preferably intravenously). The time to take effect however is comparably slow so that Lorazepam is only conditionally suitable for the acute therapy of strongly agitated patients. Lorazepam has an elimination half-life of 12–15 h, so that the maintenance of the sedation can be achieved via intermittent intravenous administrations or entirely. Since Lorazepam as well as Oxazepam unlike the other benzodiazepines is not degraded via the cytochrome P450 enzyme system there are less interactions with other drugs. Due to its poor controllability Lorazepam, similar to Diazepam and Flunitrazepam, is not suitable for deep sedation of intensive care patients.

Pharmacological effect

Benzodiazepines belong to the most used sedatives in intensive care since besides their sedating they also have an excellent anxiolytic effectiveness. Their mode of action is based on the strengthening of the inhibitory effect of the γ aminobutyric acid (GABA), particularly in the limbic system and in the formatio reticularis. GABA inhibits the activity of nerve cells and has a soothing, muscle relaxant and antispasmodic effect. Benzodiazepines therefore have a sleep-inducing as well as soporific effect. The hypnotic effect of the substances brings about a change of the REM sleep (lack of eye movements) and an impairment of deep sleep. Altogether the sleeping time is prolonged. The blocking of the perception and processing of information also prevents memorization of unpleasant events (anterograde amnesia). A retrograde amnesia however is not produced. An advantage is the broad therapeutic range of the benzodiazepines which certainly has contributed to the rapid spread and frequent application of these substances.

The significant differences between the many different combinations are their pharmacokinetic parameters, where mainly the speed of the onset of effect and the duration of the effect (elimination half-life) play a role. After oral administration clear differences in the onset of effect were observed which essentially are due to different speeds of resorption and the flooding of the CNS. A distinction is made between:

• Substances with rapid onset of effect, such as Triazolam or Diazepam, and
• Substances with delayed onset of effect, such as Oxazepam or Temazepam

Due to their elimination half-lives one differentiates in addition between long-acting (e.g. Diazepam), medium-long acting (e.g. Flunitrazepam) and short-acting (e.g. Midazolam) benzodiazepines. Particularly for the substances with half-lives, however, there is no correlation between duration of action and elimination half-life. For example, the anxiolytic or sedating effect normally does not last longer than a few hours, since the substances, similar to barbiturates, are redistributed by the CNS into the periphery. Only in a long-term therapy or with reduced elimination (reduced function of liver or kidneys) the often very long elimination half-lives have an adverse effect. Here there is a risk of accumulation of the substance.

Although benzodiazepines principally have the same active profile, they differ in potency, distribution, metabolism and whether they can be broken down to active metabolites. The biotransformation takes place in the liver, the excretion via urine and bile is often preceded by a conjugate formation (glucuronidation). Metabolization is particularly manifold: N- desalkylation, hydroxylation, deamination, reduction, acetylation, N-oxidation and hydrolysis lead to numerous partly active breakdown products. The detection time in urine with therapeutic dosing is about 3 days, in long-term consumption up to 6 weeks, in blood several hours to some days. Patient-specific factors such as concomitant diseases or alcohol abuse influence strength and duration of action of all benzodiezepines which calls for individual dosing. Old patients have generally a delayed clearance of the benzodiazepines or their active metabolites. A reduced hepatic or renal function can further prolong the elimination half-life of the benzodiazepines or their active metabolites. The induction or inhibition of hepatic or intestinal enzyme activities by other drugs influence the oxidative metabolism of most benzodiazepines.

All benzodiazepines have good anticonvulsive activity and lead centrally induced to a slight muscle relaxation. The anticonvulsive effect of the benzodiazepines is mainly based on the fact that these substances inhibit the propagation and generalization of a localized neuronal hyperactivity (focus), while to the activity of the neurons in the focus itself they show an effect only in high doses. Benzodiazepines are anticonvulsively acting acutely as well as preventatively, their anticonvulsive strength outperforms that of other antiepilectica such as Phenytoin or Carbamazepin.

Although benzodiazepines themselves are not effective analgesically they have an opioid saving effect which is caused by a change of the anticipatory pain response.

Application

Benzodiazepines should be titrated up to a previously defined endpoint, several dosages are often required. Particularly cardiac restricted or hemodynamically unstable patients (hypovolemic, sepsis, shock) react initially with pronounced hypotension (negative inotrope, peripheral vasodilatation). The maintenance of the desired sedation levels can be achieved depending on the clinical duration of action with intermittent Boli according to a defined scheme or also by applications as needed. In intensive care, in particular for long-term ventilated patients, mostly the continuous administration via motor syringe pump is preferred. Especially advantageous is the wide therapeutic applicability of the benzodiazepines.

Long-term sedation

Ceiling effects limit the applicability of the benzodiazepines to deep sedation, in particular in long-term sedation. Moreover, already after some days or even hours, a tolerance development can be observed that often leads to an excessive increase of the dosages. Early steps should therefore be taken to combine benzodiazepines with other substances such as Propofol and thereby use synergistic effects. Pharmacologically senseless increases of doses of benzodiazepines can thus be avoided.

Withdrawal syndromes and paradoxical reactions

Abrupt discontinuation of benzodiazepines frequently causes withdrawal syndromes. Especially elderly patients show an increased incidence of paradoxical reactions with agitation, insomnia and disorientation. Possibly they are a consequence of the benzodiazepine-induced change of information processing and occur especially with low dosages.

In spite of its long elimination half-life of 24 to 48 hours, Diazepam after a single dose has a rapid onset of action and a short clinical duration of action. After repeated administration, however, the duration of action rises considerably, which above all is due to the accumulation of its long-acting metabolites (Temzepam, Oxazepam ...) which have half-lives up to 80 hours.

Der Einsatz von Diazepam zur Langzeitsedierung ist daher nur mit Einschränkungen zu befürworten.

Pharmacological effect

The highly potent hypnotic Propofol is increasingly gaining acceptance as basic sedative in intensive medicine. It is available as 1% and 2% solution in a water-in-oil emulsion, with soybean oil (10%), glycerol (2.5%) and phospholipids (1.2%) as solubilizer. Due to its short duration of action (elimination half-life 20–30 min) Propofol is accurately controllable, but must be administered continuously (1.0-3.0 mg/kg/hr). The context-sensitive half-life of Propofol after a duration of infusion of 8 hours is less than 30 min. After a longer lasting administration here too an overhang occurs by back flow from tissue stores so that the context-sensitive half-life increases.

Elimination is done mainly hepatically by glucuronidation, the pharmacologically inactive metabolites are renally eliminated. The elimination kinetics are not impaired by disturbances of the kidney and liver function.

Side effects

In longer lasting application in higher doses the fat content of the emulsion (1.1 kcal/ml) if necessary has to be taken into account in the calories balance. The triglycerides in the serum could increase considerably. For this reason, the 2% solution has advantages over the 1% mix. Propofol results regularly and dose-dependent in hypotension and bradycardia, whereby the hypotension is especially pronounced after Bolus injections. In peripheral veins Propofol partly causes severe injection pain which can be alleviated by adding local anaesthetics. Generally, for long-term sedation the application via a central venous catheter is required.

After long-lasting Propofol sedation increases of the pancreatic enzymes have been described, in individual cases pancreatitis have been observed but the relation is not yet assured so far.

The rhabdomyolysis is a rare but serious and dangerous undesirable effect of Propofol. In the product information of the manufacturers it is mentioned in longer lasting application (>48 h) in intensive medicine in doses of more than 4 mg/kg/hr. Cases of rhabdomyolysis have also been described in the literature. Especially dramatic and characterized by a high mortality is the so-called Propofol-infusion syndrome, which among others includes the following symptoms: Rhabdomyolysis of the skeletal and heart muscles, (Brady-)arrhythmia up to cardiovascular failure, hypertriglyceridemia and lipemia, metabolic acidosis and kidney failure. The exact pathophysiology of this syndrome is not known. Most at risk are children. For this reason, in Germany Propofol for sedation in intensive care treatment is approved only for adults and for anaesthesia only for children aged 3 and above.

Clinical application

Originally introduced as hypnotic for total intravenous anaesthesia (TIVA), Propofol is gaining increasing acceptance as an alternative to the benzodiazepines in intensive care medicine. Due to its low context-sensitive half-life value Propofol is very well suited for short-term (deeper)ventilated patients, e.g. during night hours. In equipotent doses with volunteers Propofol caused a comparable amnesia as benzodiazepines while for intensive care patients an amnesia was less frequent than after Midazolam.

The duration of continuous application is restricted by the manufacturer to 7 days due to the above-mentioned potential side effects. Clinical experience shows that also under Propofol apparently the development of tolerance occurs. To avoid even higher doses with the above-mentioned side effects and also for cost reasons the combination with a lower dosed benzodiazepine (for example Midazolam, 5 mg/h) can be recommended. Propofol infusions without antimicrobial additive should be discarded latest after 12 hours for hygienic reasons.

For patients which under Propofol sedation have an increasing need for vasopressors or inotropic substances, unclear arrhythmia or bradycardia needing treatment, a skip test should be made and if necessary changed to another sedative.

According to the recommendations of the FDA in the USA, Propofol is to be rated as relatively safe also in the 1st trimester of pregnancy.

Similar to the benzodiazepines, Propofol has apparently anticonvulsant properties. Smaller studies and case reports point to the effectiveness of Propofol in status epilepticus, since the status could not be limited with the usual medication regimes. Repeatedly Propofol was used successfully also in the therapy of delirium tremens. Excitatory phenomena such as myoclonus are seldom observed.

In neurosurgical patients the deep sedation with Propofol – like also with other sedatives – leads to the decrease of intracranial pressures with simultaneous reduction of cerebral blood flow and brain metabolism. The advantage over other substances is the comparably short context-sensitive half-life, which intermittently permits the assessment of the neurological state (“diagnostic window“). However often very high doses are required, so that frequently a combination with other sedatives such as benzodiazepines and opioids seems sensible.

Neuroleptics such as Haloperidol, Dehydrobenzperidol or Levopromazin cause psychomotor changes characterized by damping of the emotional excitability, indifference towards external stimuli as well as diminished drive with sustained cooperation. They originate from changes on the level of the various neurotransmitter systems, in which the modulation of the dopaminergic transmission to cerebral synapses and basal ganglia presumably play a central role. Neuroleptics are metabolized mainly in the liver and have elimination half-lives of different lengths. The most essential disadvantage of all neuroleptics is the lack of anxiolytic active component. They are therefore less suitable as monotherapy for the sedation of intensive care patients.

Side effects

After the bolus administration of neuroleptics due to the α-receptors blocking effect (peripheral vasodilatation) short-term blood pressure drops may occur. Due to the dopaminergic activity mainly with neuroleptic drugs of the 1st generation, which also include Dehydrobenzperidol and Haloperidol, extrapyramidal symptoms with tardive dyskinesias and Parkinson-like symptoms can occur. In these cases, the symptoms can normally be eliminated with Biperiden. Neuroleptics lower the convulsive threshold, which has to be taken into account in the therapy of alcohol withdrawal. Very seldom the patients develop a locked-in syndrome, where the (alert!) patients are unable to perform voluntary movements. They can make themselves noticed only by vertical eye movements.

Newly occurred arrhythmia have been described with prolongation of the QT-time up to the extreme case of a “torsade-de-pointes“ tachycardia.

Clinical significance

Neuroleptics are characterized by a high antipsychotic potency and are mainly used for productive symptoms with delusional ideas, illusory misunderstanding and similar. Since neuroleptics do not create dependency they are frequently used in high doses for withdrawal syndromes with agitated and delirious states, for example with alcohol withdrawal syndrome. Due to the lack of anxiolytic active component a supplementation with benzodiazepines or Propofol in low doses is to be recommended.The most frequently used neuroleptic in intensive care nowadays is presumably Haloperidol, since Dehydrobenzperidol first was withdrawn from the market and only recently introduced again as a high-priced substance. Though Dehydrobenzperidol with 2.5 h has a significantly shorter elimination half-life than Haloperidol (18-54 h), the clinical duration of action is however considerably longer. For acutely agitated and delirious patients Haloperidol is mostly administered intermittent intravenously up to the sedation of the patient. The initial dose is for example 2 mg, followed by repetitive doses every 15 to 20 minutes, the dose being doubled each time.

Pharmacological effect

γ-hydroxybutyric acid (GHB), a substance related to the neurotransmitter γ-aminobutyric acid (GABA), can physiologically be detected in the brain tissues of mammals and presumably as independent neurotransmitter plays an important role in the induction and control of sleep. GHB exerts its hypnotic effect apparently via specific receptors, whereby the substance also influences the release of other neurotransmitters such as dopamine, serotonin and acetylcholine. GHB has no analgesic, muscle relaxant or vegetatively inhibiting effects. The onset of action after intravenous injection is very delayed and occasionally occurs only minutes after the injection. Falling asleep is felt by the patient as comfortable.

Already more than 40 years ago GHB was introduced in anaesthesia as hypnotic but could not establish itself in clinical practice due to the difficult to predict pharmacokinetics and the resulting considerably changing wake-up times.

Clinical significance

The suitability of GHB for sedation in intensive care has been controversially discussed for years. Favourable in any case is the high circulation stability which possibly is caused by a positive-inotropic mechanism. The respiratory drive is also scarcely influenced, which can be favourable in intubated patients in the weaning phase. This is contrasted by poor controllability, the lack of anxiolytics, psychomimetic side effects, in individual cases barely foreseeable quality of sedation as well as possible spasm inducing effects. Controversial issues are the postulated cerebroprotective effect of the substance, and the use in patients with increased intracranial pressure.

At present GHB is occasionally used in intensive care as alternative sedative in patients which can only be sedated insufficiently with customary schemes. The high sodium content of he substance must be considered which requires tight serum sodium controls. Even with intact kidney function this results in a limitation in long-term use. For the reduction of dosage therefore the combination with another substance like Midazolam or Propofol is mostly recommended, whereby due to synergistic effects considerable savings in dosage can be achieved. The sedative effect of GHB can be antagonized by physostigmine within 6 to 10 minutes.

The bioavailability of orally applied GHB is about 25%. Clinically this form of application no longer plays a role, on the other hand a considerable abuse potential as a party drug has developed.

Methohexital has an elimination half-life of only 1.0 to 3.0 and thus a good controllability also in long-term application. Active metabolites must not be produced during metabolism in the liver. The induction of microsomal hepatic enzyme systems (cytochrome P450) compared to thiobarbiturates (thiopental) is low. Delirious symptoms in the weaning phase after long-term therapy are rarer than after benzodiazepines. A disadvantage, however, is the narrow therapeutic range. After bolus injections Methohexital leads to a pronounced impairment of the hemodynamics. This effect is however considerably lower in continuous infusion. Influencing the thermoregulation can be advantageous under clinical intensive care conditions. Discussed is an infection-promoting effect by immunosuppression which is reinforced by the proncounced inhibition of the mucociliary clearance and the gastrointestinal motility. All barbiturates lead to hyperalgesia in low doses.

The substance is occasionally used to reduce increased pressures or also as a "brain protective" measure in ventilated patients with severe traumatic brain injury, but otherwise could not assert itself in intensive care. Continuous administration is recommended, mostly together with an opioid. By the adjuvant administration of benzodiazepines, the dose can be reduced.

For intubated and ventilated patients with persistent pain symptoms the continuous application of shorter-acting opioids with less hemodynamic and gastrointestinal side effects is preferred. The standard substance for this form of application formerly was Fentanyl, which due to its shorter duration of action compared to morphine is easier to control (elimination half-life 2.0-6.0 h). Moreover, Fentanyl does not lead to the release of histamines and can therefore be used without any problems also for patients with obstructive lung diseases.

The sedating component of Fentanyl is only slight so that normally the adjuvant administration of sedatives is necessary. The pharmacokinetics is not substantially impaired by kidney and liver dysfunctions. In longer-lasting application however the context-sensitive half-life of Fentanyl increases significantly, so that Fentanyl over the past years in intensive care has been largely displaced by substances with more favourable pharma kinetics.

In individual cases, for example in patients with chronic pain syndromes, Fentanyl can also be applied in intensive care transdermal via skin patches. The patches release the substance continuously yet the absorption is uncertain. It depends among others from body temperature, skin perfusion and skin texture. Accordingly, the plasma concentrations can vary widely. Effective analgesic concentrations are reached after hours only, so that Fentanyl patches for the therapy of acute pain states are unsuitable. After removal the action of the patch lasts for a similar period of time.

The opioid has an analgesic potency about 30 times stronger than morphine. The time to take effect of 1 to 2 minutes is relatively short. The context-sensitive half-life of Alfentanil is slightly rising for continuous infusion up to 2 hours and then remains constant for hours. The hepatic biotransformation of Alfentanil takes place via the cytochrome-P450 enzyme system, the renal excretion of the unmodified parent substance is minimal.

In hepatic impaired patients therefore the half-life is increased and an intensified and prolonged effect is to be expected. Although Alfentanil is regularily eliminated to a small extent, nevertheless with restricted renal function a dose adjustment is not necessary. Like Fentanil, over the last few years Alfentanil has increasingly been displaced by newer and pharmacologically more favourable substances such as Sufentanil and recently also by Remifentanil.

Compared to Fentanyl and Alfentanil, Sufentanil offers a number of advantages. It not only has a stronger analgesic effectiveness and more favourable hemodynamic properties but has at the same time a more favourable pharmacological profile (elimination half-life 2.7 ± 1.2 h).

In comparison with other opioids moreover the mostly undesirable linking of analgesic and respiratory depression effectiveness is known to be less pronounced.

This could be due to the comparably lower affinity of Sufentanil to the μ2 receptors which are attributable to the respiratory depression effects. In contrast the bonding to μ1 receptors is stronger, they provide the analgesic effects. Due to the sedating effect of Sufentanil the additional application of sedatives can often be dispensed with. After an infusion time of 8 hours the context-sensitive half-life of Sufentanil is in ranges as also measured for Propofol.

In longer lasting application the context-sensitive half-life increases but the pharmacological profile of Sufentanil is significantly more favourable also in the steady state than that of Fentanyl. The hepatic biotransformation mechanism is simple and remains largely preserved even with restricted liver function.

The hepatic elimination in contrast depends from the hepatic extraction on its part is determined by the hepatic perfusion. Only a very small part of the substance is excreted in the urine unchanged so that with restricted kidney function no dose adjustment is necessary.

Due to its excellent controllability Remifentanil offers significant advantages over other opioids. The extremely short duration of action among others is the metabolism of Remifentanil: after intravenous injection Remifentanil – independently from the liver and kidney function – is hydrolytically split for 98% by ubiquitously available unspecific esterase’s in blood and tissue and for 2% eliminated by N-dealkylation.

Thereby the degradation of the substance takes place practically independently from the duration of action and dosing. The context-sensitive half-life for Remifentanil is indicated with 3 to 4 minutes. The metabolites arising during degradation have only a minimum analgesic potency and are excreted unchanged via the kidneys. A dose adjustment with kidney insufficient patients is therefore not required to current knowledge. The same applies to patients with hepatic insufficiency. Although the respiratory depressive effect should be more pronounced here.

The rapid onset of action is based on the low lipid solubility of the substance which leads to a short equilibration time between blood and brain within the central compartment. At the same time the accumulation in the adipose tissue is significantly lower than in other opioids which offers advantages especially in longer application. Favourable is also the low plasma protein bonding of about 70% to the traditional opioids compared to Fentanyl, Alfentanil and Sufentanil.

As with the other opioids also with the combination with sedatives such as benzodiazepines or Propofol a strengthening of the sedation and hemodynamic influence is to be expected so that a dose adjustment of the centrally damping drugs can be required. The duration of action of Remifentanil is largely independent from age but with geriatric patients a dose reduction is recommended.

Ketamine is the only intravenous anaesthetic that in sub-anaesthetic doses has excellent analgesic properties. Depending on the dose the substance creates a kind of cataleptic condition (“dissociative anaesthesia"), in which the patient feels detached from his environment. The stimuli received via the sense organs are forwarded unchanged but they are no longer appropriately processed by the brain. EEG studies point out that Ketamine cause a functional dissociation between the limbic and the thalamoneocortical system. This condition is accompanied by a pronounced analgesia and amnesia. Unlike other anaesthetics, Ketamine when used in clinical doses does not cause a dose-dependent suppression of the spontaneous electrical activity of the brain. There are reports about disturbing changes in body model, feelings and moods, for example weightless floating in space or nightmare scenes. Without simultaneous administration of sedatives, depending on the injected dose, frequently bizarre, partly fearsome dreams and optical hallucinations are described.

After intravenous bolus application of Ketamine (0.25-1.0 mg/kg) the onset of action is speedy. The duration of action is short (5 to 20 min), the elimination half-life is 1 to 3 hours. For interventions above 10 to 15 min mostly repetitive doses of 0.25 to 0.5 mg/kg are necessary. In individual cases, for example children without intravenous access, the intramuscular application (2 to 5 mg/kg) is also possible. Respiratory drive and cardiovascular functions are little affected even with higher doses. However, in continuous application accumulation occurs.

In intensive care, Ketamine is frequently administered in short painful interventions, for example dressing changes for burn patients, necrosis removal etc. In emergency medicine, Ketamine due to its sympathomimetic effects in patients with unstable circulation (shock, trauma, hypovolemia etc.) is the right analgesic / anaesthetic. On the other hand, with higher doses, the partly undesirable side effects such as pulmonary and systemic hypertension as well as tachycardia can occur. Since Ketamine has specific bronchodilatatory effects, it is used in ventilated patients in the status asthmatics. Due to partly excessive hypersalivation the simultaneous administration of Atropine or Glycopyrronium is recommended. Since Ketamine has only little influence on intestinal motility, the substance is a good alternative to opioids especially for patients with existing or threatening ileus symptom. A disadvantage is the psychomimetic side effects which - above all with higher doses - require he combination with benzodiazepines or Propofol.

Previously Ketamine was available only as racemic mixture of the two enantiomers (S and R)-Ketamines. For some years S(+)-Ketamine is also available which compared with the conventional Ketamin has an analgesic and anaesthetic power 2 to 3 times higher. Due to the higher clearance S(+)-Ketamin in continuous infusion is easier to control than the racemate: with comparable onset of action the wake-up times are significantly shorter. So far it is not clear whether the psychomimetic side effects are lower. It can be assumed that S(+)-Ketamine will completely replace racemate in clinical routine.

A combination of opioids with non-opioid analgesics can be sensible for the expansion of the effect spectrum (e.g. antiphlogistic effect of NSAID, spasmolytic and antipyretic effect of Metamizol) and for dose reduction of opioids with consecutive reduction of specific side effects, although systematic studies on the use of these substances in critically ill patients are not available so far.

Though Paracetamol is for years introduced for the treatment of lighter pain, yet had little importance in operative medicine. Due to the introduction of the parenteral form of application Paracetamol has in recent times experienced something of a renaissance especially in the treatment of postoperative pain. Due to ceiling effects the analgesic effectiveness of all non-opioid analgesics is restricted to the treatment of mild to moderate pain. However, the combination with an opioid lead to a stronger analgesia than higher dosed opioids alone.

Generally, all non-opioid analgesics have an opioid-saving effect which is stated to be up to 30 to 40%. The extent of this effect depends on the intensity of the pains: in patients with severe pains the effects are apparently lower than in patients with moderate pains.

On the whole the status of the oral and also the parenteral analgesics in intensive care is still unclear at present.